Piperazine derivatives and pharmaceutical composition containing them

ABSTRACT

Piperazine derivatives or pharmaceutically acceptable acid addition salts thereof are useful as neuroleptic, anti-hypertensive or bradycardic agents.

The present invention relates to piperazine derivatives, theirproduction and pharmaceutical compositions containing them.

According to the present invention there are provided compounds offormula I, ##STR1## wherein one of A and B is N and the other CH, Z is aring sharing two ring carbon atoms with the ring containing A and B andhaving the formula II or III, ##STR2## R₁ and R₂ are each,independently, hydrogen, (C₁₋₆)alkyl or (C₇₋₁₀)phenylalkyl, optionallymonosubstituted in the phenyl ring by halogen, (C₁₋₄)alkyl or(C₁₋₄)alkoxy,

R₃ is hydrogen or (C₁₋₄)alkyl,

R₁ ' and R₂ ' signify hydrogen or (C₁₋₄)alkyl, or

R₁ ' and R₂ ' together signify trimethylene, tetramethylene orpentamethylene,

m is 1 or 2,

R₄ and R₅ are each, independently, hydrogen, halogen, (C₁₋₄)alkyl,(C₁₋₄)alkoxy, (C₂₋₄)acyl or trifluoromethyl, and

X is --CH₂ -- and n is 0, 1, 2 or 3, or

X is --CO-- and n is 1, 2 or 3, or

X is --O-- and n is 2 or 3,

and acid addition salts thereof.

In formula I R₃ is attached to a ring carbon atom. Halogen meansfluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

Most suitably R₄ is para to the X moiety. R₄ is preferably halogen,especially fluorine. R₅ is preferably hydrogen or halogen. Suitably X is--O-- but more suitably X is --CO--. Particularly suitable values for nare 2 or 3 preferably 3. A preferred value for m is 1. R₁ ' and R₂ ' arepreferably the same.

The present invention also provides a process for the production of acompound of formula I, which comprises

(a) producing a compound of formula Ia, ##STR3## wherein A, B, R₁ -R₅,X, m and n are as defined above, by reacting a compound of formula IV,##STR4## wherein A, B, R₁, R₃ -R₅, m and n are as defined above, and X'has the same significance as X, whereby if desired the carbonyl group isprotected, with a compound of formula V, ##STR5## wherein R₂ is asdefined above, and either (i) Y and Z together with the carbon atom towhich they are bound are >C═O and U is a leaving group, or

(ii) Y, Z and U are leaving groups,

or

(b) producing a compound of formula Ib, ##STR6## wherein A, B, R₁ ', R₂', R₃ -R₅, X, m and n are as defined above, by reacting a compound offormula IV wherein R₁ is hydrogen, with a compound of formula VI,##STR7## wherein R₁ ' and R₂ ' are as defined above, and subsequentlyremoving any carbonyl-protecting group present.

Compounds of formula Ia wherein R₁ is hydrogen, may exist in atautomeric form of formula Ia', ##STR8## Such tautomeric forms are alsoencompassed in the present compounds of formula I.

Process (a) may be effected in conventional manner for analogous ringclosure reactions e.g. by condensation. A suitable reaction temperatureis 40° to 200°, preferably 80° to 140°. The reaction may, if desired,also be carried out in the presence of an inert organic solvent.Suitable solvents include tetrahydrofuran, dioxan, methylethylketone,dimethylsulfoxide, n-propanol, toluene or N-methylpyrrolidone. An excessof a compound of formula V may be employed to provide the reactionmedium. In the compounds of formula V U is e.g. halogen, especiallychlorine or bromine, hydroxy, (C₁₋₄)alkoxy, amino, di(C₁₋₄)alkylamino or--O--CO--R₂. The reaction is conveniently carried out in the presence ofan acid, such as hydrochloric acid or polyphosphoric acid, when Y and Ztogether with the carbon atom to which they are bound are >C═O and U ishydroxy, (C₁₋₄)alkoxy, amino or di(C₁₋₄)alkylamino. When Y, X and Z areleaving groups then they are preferably (C₁₋₄)alkoxy.

Compounds of formula Ia may also be obtained by cyclising a compound offormula VII, ##STR9## wherein A, B, R₁ -R₅, X', m and n are as definedabove. The cyclisation may be effected at temperatures between 60° to230°, preferably 100° to 150°. The reaction may be performed in thepresence or absence of a solvent. Suitable solvents include dioxane,dimethylsulfoxide, n-propanol, toluene or N-methylpyrrolidone.

Conveniently an acid such as hydrochloric or polyphosphoric acid ispresent. The cyclisation may also be effected without an acid.

Process (b) may be effected in conventional manner for analogous ringcondensations. The process is conveniently carried out at a temperaturein the range from 40° to 160°, preferably 60° and 120°. Suitablesolvents include methanol, tetrahydrofuran, dioxan, toluene orn-propanol.

Where X is --CO-- in the resulting compound of formula I, it may beconvenient to use a carbonyl-protecting group, e.g. a dialkylketal groupsuch as dimethyl or diethyl ketal group, or a alkylene ketal group suchas ethylene or n-propylene ketal group. The removal of such group can beeffected in known manner.

Compounds of formula IV may, for example, be obtained via the followingreaction scheme: ##STR10##

Any carbonyl-protecting group can be removed in known manner eitherbefore condensation with a compound of formula V or VI or afterwards.

Compounds of formula VII may be obtained by reacting a compound offormula IV with a compound of formula V. The reaction is convenientlycarried out in presence of an acid binding agent such as triethylamineor pyridine. Suitable temperatures may be from 0° to 60°, preferably 20°to 40°. The reaction may be effected in absence or presence of an inertorganic solvent. Suitable solvents include toluene, n-propanol, dioxanor N-methylpyrrolidone. The resulting compounds of formula VII can becyclised in situ to compounds of forumula Ia by suitable regulation ofthe reaction temperature.

The reaction may be followed by conventional means, e.g. thin layerchromatography to determine when satisfactory yields of a compound offormula VII or Ia are obtained.

Insofar as the production of starting materials is not particularlydescribed these compounds are known or may be produced in analogousmanner to known compounds or to processes described herein.

The compounds of formula VII, wherein A, B, R₁ -R₅, m and n are asdefined above and X' is --CH₂ --, --CO-- or --O-- are of particularinterest.

The compounds of formulae I and VII may be converted into acid additionsalts thereof in conventional manner and vice versa. Suitable acidsinclude for example, hydrochloric acid, hydrobromic acid, succinic acid,maleic acid or fumaric acid.

In the following examples all temperatures are given in degreesCentigrade and are uncorrected.

In the Tables the following abbreviations are used:

(2) bis-maleate

(3) hydrochloride

(4) dihydrochloride

(5) decomposition

EXAMPLE 11-(4-Fluorophenyl)-4-[4-(1H-imidazo[4,5-b]pyridin-5-yl)-1-piperazinyl]-1-butanone[compound Ia]

9 g1-(4-Fluorophenyl)-4-[4-(2,3-diamino-pyridin-6-yl)-1-piperazinyl]-1-butanoneand 60 ml (98%) formic acid are boiled for 5 hours. The mixture isdiluted with 80 ml water and made alkaline at room temperature withconc. sodium hydroxide solution. The precipitate is filtered off, washedwith water, dried and dissolved in hot ethyl acetate. The hot solutionis treated with active carbon and filtered. The title compound isprecipitated on cooling, m.p. 166°-167°.

Purification may be effected by chromatography on silica-gel withacetone as eluant.

The starting material may be obtained as follows:

6 g 2-amino-6-chloro-3-nitropyridine, 12.6 g1-(4-fluorophenyl)-4-(1-piperazinyl)-1-butanone dihydrochloride and 20 gpotassium carbonate in 120 ml n-propanol are stirred under reflux for21/2 hours. The mixture is then treated with 400 ml water, stirred forfurther 10 minutes and cooled in ice bath. The resulting precipitate isfiltered off, washed with water, dissolved in methylene chloride, driedover sodium sulphate and evaporated. The resulting1-(4-fluorophenyl)-4-[4-(2-amino-3-nitro-pyridin-6-yl)-1-piperazinyl]-1-butanone,m.p. 128°-130°, is without further purification dissolved in 400 mlmethanol. 3 g palladium on charcoal (5%) are added to the solution andthe mixture is hydrogenated under normal conditions. The catalyst isfiltered off and the solvent distilled off to give1-(4-fluorophenyl)-4-[4-(2,3-diaminopyridin-6-yl)-1-piperazinyl]-1-butanonewhich is used without further purification.

EXAMPLE 2 1-(4-Fluorophenyl)-4-[4-(1Hazinyl]-1-butanoneidin-5-yl)-1-piper[compound Ia]

7.5 g1-(4-Fluorophenyl)-4-[4-(2,3-diamino-pyridin-6-yl)-1-piperazinyl]-1-butanoneethylene ketal and 50 ml (99%) formic acid are refluxed for 5 hours. Theformic acid is then distilled off. The residue is diluted with the 2fold amount of water and made alkaline with conc. sodium hydroxidesolution. The resulting precipitate is filtered off, washed with waterand taken up with 80 ml hot acetone. The solution is filtered, andcooled. The precipitate is filtered off and recristallised from ethylacetate using active charcoal to give the title compound, m.p.167°-168°.

The starting material may be obtained as follows:

(a)1-(4-Fluorophenyl)-4-[4-(2-amino-3-nitro-pyridin-6-yl)-1-piperazinyl]-1-butanoneethylene ketal

5.6 g 2-amino-6-chloro-3-nitropyridine, 10 g1-(3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-propyl)piperazine, 5 gpotassium carbonate and 100 ml n-propanol are refluxed 21/2 hours. Aftercooling the precipitate is filtered off. The filtrate is concentrated toca. 10 ml and diluted with the same volume of diisopropyl ether. Theresulting cristallisate is admixed with the above mentioned precipitateand partitioned between water and methylene chloride. The organic phaseis filtered and evaporated to give the heading compound, m.p. 117°-118°.

(b)1-(4-Fluorophenyl)-4-[4-(2,3-diamino-pyridin-6-yl)-1-piperazinyl]-butanoneethylene ketal

12 g of the example (a) compound are dissolved with heating in 1200 mlmethanol. After addition of 1 g palladium on charcoal (5%) the mixtureis hydrogenated under normal conditiions. The catalyst is filtered offand the solution is evaporated to give the heading compound, which canbe used without further purification. M.p. 118°-119° (recrystallisedfrom ethyl acetate/diisopropyl ether).

EXAMPLE 3

In analogous manner to that disclosed in Example 1 the followingcompounds of formula Ia are produced wherein m is 1 and R₃ is hydrogenvia the corresponding compounds of formula VII:

    __________________________________________________________________________    Example                                                                            A  B R.sub.1                                                                             R.sub.2                                                                             n X  R.sub.4                                                                          R.sub.5                                                                         m.p.                                          __________________________________________________________________________    a    CH N CH.sub.3                                                                            H     0 CH.sub.2                                                                         H  H 114-115                                       b    CH N CH.sub.3                                                                            H     3 CO 4-F                                                                              H 118-119                                       c    CH N H     CH.sub.3                                                                            3 CO 4-F                                                                              H 176-178                                       d    CH N CH.sub.3                                                                            CH.sub.3                                                                            3 CO 4-F                                                                              H 152-154                                       e    CH N CH(CH.sub.3).sub.2                                                                  H     3 CO 4-F                                                                              H  97-98                                        f    CH N CH.sub.2 C.sub.6 H.sub.5                                                            H     3 CO 4-F                                                                              H 110-112                                       g    CH N CH.sub.3                                                                            H     1 CH.sub.2                                                                         H  H 124-126                                       h    CH N H     H     3 O  4-F                                                                              H 150-153                                       i    CH N H     C.sub.2 H.sub.5                                                                     3 CO 4-F                                                                              H 152-153                                       j    CH N H     n-C.sub.3 H.sub.7                                                                   3 CO 4-F                                                                              H >228.sup.(4)(5)                               k    CH N H     CH(CH.sub.3).sub.2                                                                  3 CO 4-F                                                                              H 240-250.sup.(3)(5)                            l    CH N CH.sub.3                                                                            n-C.sub.3 H.sub.7                                                                   3 CO 4-F                                                                              H 131-133                                       m    CH N CH.sub.3                                                                            CH(CH.sub.3).sub.2                                                                  3 CO 4-F                                                                              H 128-129                                       n    CH N H     CH.sub.2 C.sub.6 H.sub.5                                                            3 CO 4-F                                                                              H                                               o    CH N H     CH.sub.3                                                                            3 O  4-F                                                                              H 186-190                                       p    CH N H     C(CH.sub.3).sub.3                                                                   3 CO 4-F                                                                              H                                               q    CH N C.sub.2 H.sub.5                                                                     H     3 CO 4-F                                                                              H  85-87                                        qq   CH N CH.sub.3                                                                            C.sub.2 H.sub.5                                                                     3 CO 4-F                                                                              H 134-135                                       r    N  CH                                                                              H     H     3 CO 4-F                                                                              H 184-185                                       s    N  CH                                                                              H     CH.sub.3                                                                            3 CO 4-F                                                                              H 180-183                                       t    N  CH                                                                              H     H     3 O  4-F                                                                              H 182-183.5                                                                     163-164.5.sup.(2)(5)                          u    N  CH                                                                              H     C.sub.2 H.sub.5                                                                     3 CO 4-F                                                                              H 201-205                                       v    N  CH                                                                              H     CH(CH.sub.3).sub.2                                                                  3 CO 4-F                                                                              H 195-197                                       w    N  CH                                                                              CH.sub.3                                                                            CH.sub.3                                                                            3 CO 4-F                                                                              H 188-190                                       x    N  CH                                                                              CH.sub. 3                                                                           H     3 CO 4-F                                                                              H 177.5-178.5                                   y    N  CH                                                                              CH(CH.sub.3).sub.2                                                                  H     3 CO 4-F                                                                              H                                               z    N  CH                                                                              H     CH.sub.2 C.sub.6 H.sub.5                                                            3 CO 4-F                                                                              H 225-240.sup.(4)(5)                            vv   N  CH                                                                              H     CH.sub.3                                                                            3 O  4-F                                                                              H                                               __________________________________________________________________________

EXAMPLE 44-[4-(4,5-Diacetylamino-2-pyridinyl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone[compound VII]

8.3 g1-(4-Fluorophenyl)-4-[4-(4,5-diamino-pyridin-2-yl)-1-piperazinyl]-1-butanoneare stirred for 20 hours with 4.5 ml acetyl chloride, 9 ml triethylamineand 150 ml toluene at room temperature. The precipitate is filtered offand dissolved in 2N HCl. The solution is treated with active charcoal,filtered and made alkaline with aqueous NH₃. The resulting precipitateis washed with a little volume of ether and ethanol and isrecrystallized from ethanol to give the title compound, m.p. 206°-209°.(dried in high vacuo above 120°).

The starting material may be prepared as described in Example 1 startingfrom 4-amino-2-chloro-5-nitro-pyridine via1-(4-fluorophenyl)-4-[4-(4-amino-5-nitro-pyridin-2-yl)-1-piperazinyl]-1-butanoneto give1-(4-fluorophenyl)-4-[4-(4,5-diamino-pyridin-2-yl)-1-piperazinyl]-1-butanone,m.p. 166°-169° (from ethyl acetate).

EXAMPLE 5

In analogous manner to that disclosed in Example 4 the followingcompounds of formula VII are produced wherein m is 1 and R₃ is hydrogen:

    __________________________________________________________________________    Example                                                                            A  B  R.sub.1                                                                             R.sub.2                                                                             n X  R.sub.4                                                                          R.sub.5                                                                         m.p.                                         __________________________________________________________________________    a    CH N  CH.sub.3                                                                            H     0 CH.sub.2                                                                         H  H                                              b    CH N  CH.sub.3                                                                            H     3 CO 4-F                                                                              H                                              c    CH N  H     CH.sub.3                                                                            3 CO 4-F                                                                              H 124-127                                      d    CH N  CH.sub.3                                                                            CH.sub.3                                                                            3 CO 4-F                                                                              H 179                                          e    CH N  CH(CH.sub.3).sub.2                                                                  H     3 CO 4-F                                                                              H                                              f    CH N  CH.sub.2 C.sub.6 H.sub.5                                                            H     3 CO 4-F                                                                              H                                              g    CH N  CH.sub.3                                                                            H     1 CH.sub.2                                                                         H  H                                              h    CH N  H     H     3 O  4-F                                                                              H                                              i    CH N  H     C.sub.2 H.sub.5                                                                     3 CO 4-F                                                                              H 112-114                                      j    CH N  H     n-C.sub.3 H.sub.7                                                                   3 CO 4-F                                                                              H                                              k    CH N  H     CH(CH.sub.3).sub.2                                                                  3 CO 4-F                                                                              H 133-136                                      l    CH N  CH.sub.3                                                                            n-C.sub.3 H.sub.7                                                                   3 CO 4-F                                                                              H                                              m    CH N  CH.sub.3                                                                            CH(CH.sub. 3).sub.2                                                                 3 CO 4-F                                                                              H                                              n    CH N  H     CH.sub.2 C.sub.6 H.sub.5                                                            3 CO 4-F                                                                              H                                              o    CH N  H     CH.sub.3                                                                            3 CO 4-F                                                                              H                                              p    CH N  H     C(CH.sub.3).sub.3                                                                   3 CO 4-F                                                                              H                                              q    CH N  C.sub.2 H.sub.5                                                                     H     3 CO 4-F                                                                              H                                              r    N  CH H     H     3 CO 4-F                                                                              H 155-157                                      s    N  CH H     CH.sub.3                                                                            3 O  4-F                                                                              H   178-179.5                                  t    N  CH H     H     3 O  4-F                                                                              H                                              u    N  CH H     C.sub.2 H.sub.5                                                                     3 CO 4-F                                                                              H 183-185                                      v    N  CH H     CH(CH.sub.3).sub.2                                                                  3 CO 4-F                                                                              H                                              w    N  CH CH.sub.3                                                                            CH.sub.3                                                                            3 CO 4-F                                                                              H 192-193                                      x    N  CH CH.sub.3                                                                            H     3 CO 4-F                                                                              H                                              y    N  CH CH(CH.sub.3).sub.2                                                                  H     3 CO 4-F                                                                              H                                              z    N  CH H     CH.sub.2 C.sub.6 H.sub.5                                                            3 CO 4-F                                                                              H                                              __________________________________________________________________________

EXAMPLE 61-(4-Fluorophenyl)-4-[4-(2-methyl-1H-imidazo[4,5-c]pyridin-6-yl]-1-piperazinyl]-1-butanone(compound Ia from compound of formula VII)

5 g4-[4-(4,5-Diacetylamino-2-pyridinyl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanoneand 25 g polyphosphoric acid are stirred and heated 1 hour at 140°. Thereaction mixture is then cooled to room temperature, treated with 200 mlwater, made alkaline with aqueous NaOH solution and extracted withmethylene chloride. The extract is dried and evaporated. The residue isrecrystallized from dichlormethane/diisopropylether to give the titlecompound, m.p. 180°-183°. M.p. of the bis-maleate 172°-173.5°.

EXAMPLE 74-[4-(2,3-Dimethyl-pyrido[2,3-b]pyrazin-6-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone(compound Ib)

9 g4-[4-(2,3-Diamino-pyridin-6-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanoneand 2.6 g butane-2,3-dione in 250 ml methanol are stirred under refluxfor 1 hour. The solvent is evaporated. The residue is dissolved in hotethyl acetate and treated with active charcoal, filtered and cooled togive the title compound, m.p. 155°-156°.

EXAMPLE 8

In analogous manner to that disclosed in Example 7 the followingcompounds of formula Ib are produced wherein m is 1 and R₃ is hydrogen:

    ______________________________________                                        Ex-                                                                           am-                                                                           ple  A      B      R.sub.1 '                                                                             R.sub.2 '                                                                          n   X    R.sub.4                                                                            R.sub.5                                                                           m.p.                        ______________________________________                                        a    CH     N      H       H    3   CO   4-F  H   130-                                                                          131                         b    CH     N      C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                                                                    3   CO   4-F  H    99-                                                                          100                         c    N      CH     CH.sub.3                                                                              CH.sub.3                                                                           3   CO   4-F  H   138-                                                                          139                         d    N      CH     H       H    3   CO   4-F  H   124-                                                                          126                         e    N      CH     C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                                                                    3   CO   4-F  H   118-                                                                          121                         f    N      CH     --(CH.sub.2).sub.4 --                                                                    3   CO   4-F  H   138-                                                                          140                           g    N      CH     H       H    3   O    4-F  H    98-                                                                          100                         ______________________________________                                    

EXAMPLE 9

In analogous manner to that disclosed in Example 1 the followingcompounds of formula Ia may be prepared:

    __________________________________________________________________________    Ex.                                                                              A  B  R.sub.1        R.sub.2        R.sub.3                                                                            m n X  R.sub.4                                                                             R.sub.5              __________________________________________________________________________    a  CH N                                                                                 ##STR11##     H              7-nC.sub.3 H.sub.7                                                                 1 3 CH.sub.2                                                                         3-Cl  5-Cl                 b  CH N  H                                                                                             ##STR12##     6-nC.sub.4 H.sub.9                                                                 1 1 CH.sub.2                                                                         3-OC.sub.2 H.sub.5                                                                  5-OC.sub.2                                                                    H.sub.5              c  N  CH C.sub.2 H.sub.5                                                                               ##STR13##     4-CH.sub.3                                                                         2 3 O  3-COC.sub.2 H.sub.5                                                                 H                    __________________________________________________________________________

EXAMPLE 10

In analogous manner to that disclosed in Example 7 the followingcompounds of formula Ib may be prepared:

    __________________________________________________________________________    Example                                                                            A  B  R.sub.1 '                                                                         R.sub.2 '                                                                         R.sub.3                                                                           m n X  R.sub.4                                                                            R.sub.5                                    __________________________________________________________________________    a    CH N  H   H   8-C.sub.2 H.sub.5                                                                 1 2 O  3-Cl 5-Cl                                       b    CH N  --(CH.sub.2).sub.3 --                                                                 H   2 3 CH.sub.2                                                                         3-CF.sub.3                                                                         H                                          c    N  CH C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   5-CH.sub.3                                                                        1 2 CH.sub.2                                                                         2-OCH.sub.3                                                                        H                                          __________________________________________________________________________

EXAMPLE 11

In analogous manner to that disclosed in Example 4 the followingcompounds of formula VII may be prepared:

    __________________________________________________________________________    Ex.                                                                              A  B  R.sub.1        R.sub.2        R.sub.3                                                                            m n X  R.sub.4                                                                             R.sub.5              __________________________________________________________________________    a  CH N                                                                                 ##STR14##     H              4-nC.sub.3 H.sub.7                                                                 1 3 CH.sub.2                                                                         3-Cl  5-Cl                 b  CH N  H                                                                                             ##STR15##     5-nC.sub.4 H.sub.9                                                                 1 1 CH.sub.2                                                                         3-OC.sub.2 H.sub.5                                                                  5-OC.sub.2                                                                    H.sub.5              c  N  CH C.sub.2 H.sub.5                                                                               ##STR16##     2-CH.sub.3                                                                         2 3 O  3-COC.sub.2 H.sub.5                                                                 H                    __________________________________________________________________________

The compounds of formulae I and VII are useful because they possesspharmacological activity in animals and are therefore useful aspharmaceuticals, e.g. for therapy. In particular, the compounds offormulae I and VII are useful as neuroleptic agents in the treatment ofe.g. psychotic disorders such as schizophrenia, as indicated in standardtests, e.g. by an inhibition of locomotion in mice. In this test groupsof 3 male mice (18-24 g, OF-1, Sandoz Basle) received 3.2, 10, 32, 100and 320 mg p.o. of the test drug. 1 hour after drug administration themice were observed individually and their locomotion compared with thatof control. The locomotion of the animals was observed and the ED_(min)(the minimum dose at which significant inhibition was observed)determined.

The compounds of formulae I and VII bind further on ³ H-Spiperonebinding sites in the brain [modified method of J. Leysen et al.,Biochem. Pharmac. 27, 307 (1978)]. The test was performed as follows:fresh calf brain striatal tissue was homogenized in the 25 fold volumeof Tris buffer (pH 7.4, 50 mM, 120 mM sodium chloride) and centrifuged.The pellets were suspended in the 22 fold volume of Tris buffer,incubated for 15 minutes at 37° C. and centrifuged. The pellets weresuspended in the 300 fold volume of Tris buffer. The composition of theassay mixtures was as follows: 45 mM Tris buffer pH 7.7, 108 mM sodiumchloride, membranes corresponding to 6 mg of original tissue weight, 0.1nM ³ H-Spiperone, 5×10⁻⁷ M Cinanserin to eliminate the contribution of5-HT₂ receptors and 1 μM unlabelled Spiperone for the determination ofnon-specific binding. To determine the inhibition of the specificbinding of ³ H-Spiperone the test drugs were added to give 5 to 9different concentrations between 1 nM and 10 μM, each in duplicate.After incubation for 40 minutes at room temperature, the assay mixtureswere raidly filtered through Whatman GF/B filter, the filters washedtwice with 5 ml of ice cold Tris buffer and scintillation-counted. TheIC₅₀ values (concentration of a test drug which inhibits specificbinding of ³ H-Spiperone by 50%) are determined by linear regressionanalysis. Values for representative compounds in the above tests aregiven below:

    ______________________________________                                                    Locomotor                                                                     inhibition                                                                              Receptor binding                                                    ED.sub.min                                                                              IC.sub.50 nM                                            Example     mg/kg p.o.                                                                              .sup.3 H--Spiperone                                     ______________________________________                                        1           1         306                                                     3r          ≦3.2                                                                             441                                                     5c          1         4600                                                    7           10        205                                                     8c          10        121                                                     3i          3.2       246                                                     Clozapine   3.2       990                                                     ______________________________________                                    

For the above mentioned use the dosage will, of course, vary dependingon the compound employed, mode of administration and therapy desired.However, in general, satisfactory results are obtained with a dailydosage of from about 0.1 mg to about 100 mg per kg animal body weight,conveniently given in divided doses 2 to 4 times a day or in sustainedrelease form. For the larger mammals, the total daily dosage is in therange from about 25 mg to about 600 mg, and dosage forms suitable fororal administration comprise from about 6 mg to about 300 mg of thecompounds admixed with a solid or liquid pharmaceutical carrier ordiluent.

The compounds of formulae I and VII are furthermore useful asanti-hypertensive agents, as indicated in standard tests, for example inthe ³ H-Prazosin binding assay for α₁ -receptors [modified method ofGreengrass P., et al., Eur. J. Pharmac. 55, 323-326 (1979)]. The testwas performed as follows:

Fresh calf brain cortex tissue is homogenized in a 20 fold volume ofTris-HCl buffer (50 mM, pH 7.7), using a Polytron PT 20, and centrifugedat 30'000 xg for 25 min. The pellets are resuspended in a 13 fold volumeof the same buffer, incubated for 15 min at 37° C., and recentrifuged at50'000 xg for 11 min. The pellets of this centrifugation are frozen at-20° C. and resuspended in a 60 fold volume of the same buffer as abovebefore use for the binding experiment. The composition of the assaymixtures (total volume=2 ml) is as follows: 50 mM Tris-HCl pH 7.7,membranes corresponding to 30 mg of original tissue weight, and 0.3 nM ³H-Prazosin. The assays for the definition of nonspecific bindingadditionally contain phentolamine at a concentration of 10 μM. To assessthe potency of drugs in inhibiting specific ³ H-Prazosin binding(difference between total and nonspecific binding), the test compoundsare added to give 5 to 9 different concentrations between 1 nM and 10μM, each in duplicate. After incubation for 40 min at room temperature,the assay mixtures are rapidly filtered through Whatman GF/B filters andwashed twice with 5 ml of ice cold Tris buffer. The radioactivity of thefilters is estimated by scintillation counting. For example the IC₅₀ ofthe Example 4 compound is <1 nM, of the Example 3d compound is 2.2 nMand of Guanfacine 3700 nM.

In another test female normotonic rats (200-350 g, Sprague-Dawley,Suddeutsche Tierfarm, Tuttlingen, FRG) were anaesthetized with urethane(1.5-1.75 g/kg i.p. in 2 portions) and a tracheal cannula was inserted.Blood pressure and heart rate were recorded from the carotid artery byconventional methods. Test drug were administered by the jugular or thefemoral vein. Body temperature was maintained at 37° C. by means of atemperature regulator (Alfos MK-4) triggered by a thermistor on theanimal. After adaptation, increasing doses of the test drug wereinjected i.v. to give the following cumulative doses: 3, 13, 43, 143,343 and 1443 μg/kg. ED 75% is the dose required to reduce the bloodpressure on the heart rate to 75% of pretreatment values. It wasobtained through interpolation. The ED₇₅ of the Example 4 compound is 6μg, of Example 5s compound 3 μg, of Example 8 g 4 μg and of Guanfacine57 μg.

For this use the dosage will, of course, vary depending on the compoundemployed, mode of administration and condition to be treated. However,in general, satisfactory results are obtained with a daily dosage offrom about 0.01 to about 30 mg per kg animal body weight, convenientlygiven in divided doses 2 to 4 times a day, or in sustained release form.For the larger mammals the total daily dosage is in the range from about5 to about 100 mg and dosage forms suitable for oral administrationcomprise from about 1 to about 50 mg of the compound admixed with asolid or liquid pharmaceutical carrier or diluent.

The compounds of formulae I and VII possess further bradycardiacactivity, as indicated in standard tests. For example, in guinea-pigatria in vitro [method of R. P. Hof and G. Scholtysik, J. ofCardiovascular Pharmacology 5, 176-183 (1983)] a decrease of the heartrate of spontaneously beating atria is observed at a bath concentrationof from about 1 μM to about 100 μM. The concentration decreasing therate of the spontaneously beating atria by 25% (EC₂₅ values) for somecompounds of the present invention and the standard Alinidin are givenin the following Table:

    ______________________________________                                        Compound      EC.sub.25 μM                                                 ______________________________________                                        1             7.8                                                             8d            4.0                                                             8g            2.15                                                            Alinidin      6.5                                                             ______________________________________                                    

The compounds of formulae I and VII are therefore useful as bradycardicagents, e.g. for the prophylaxis and treatment of cardiac disorders suchas Angina pectoris or heart rhythm disturbances such as sinustachycardia.

For this use the dosage will, of course, vary depending on the compoundsemployed, mode of administration and therapy desired. However, ingeneral, satisfactory results are obtained with a daily dosage of fromabout 0.05 mg to about 2 mg per kg animal body weight, convenientlygiven in divided doses 2 to 4 times a day or in sustained release form.For the larger mammals, the total daily dosage is in the range fromabout 10 mg to about 100 mg, and dosage forms suitable for oraladministration comprise from about 2 mg to about 50 mg of the compoundsadmixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds of formulae I and VII may be administered in similarmanner to known standards for use in the above-mentioned utilities, forexample, for the neuroleptic activity, Clozapine. The suitable dailydosage for a particular compound will depend on a number of factors suchas its relative potency of activity. It has for example been determinedthat the preferred compounds of this invention, the Example 1 andExample 3i compounds, produce stronger effects in the ³ H-Spiperonebinding test than Clozapine. This indicates that the compounds ofExamples 1 and 3i may be administered at similar or lower dosages tothat of Clozapine for the neuroleptic indication.

For the neuroleptic use the daily oral dosage for the compound ofExample 1 and 3i is indicated to be from 50 to 600 mg.

The compounds of formulae I and VII may be administered inpharmaceutically acceptable acid addition salt form. Such acid additionsalts exhibit the same order of activity as the free base forms. Thepresent invention also provides a pharmaceutical composition comprisinga compound of formulae I or VII or a pharmaceutical acceptable acidaddition salt thereof, in association with a pharmaceutical carrier ordiluent. Such compositions may be in the form of, for example, asolution or a tablet.

The neuroleptic activity is the preferred indication for the compoundsof formula I. In this indication the preferred compounds are the Example1 and 3i compounds.

The bradycardiac activity is the preferred indication for the compoundsof formula VII. Preferred in this indication is the compound of Example8g.

In one group of compounds of formula I A is CH, B is N, Z is a ring offormula II, R₁, R₂ and R₃ are each, independently, hydrogen or(C₁₋₄)alkyl, m is 1, R₄ and R₅ are each, independently, hydrogen,halogen, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₂₋₄)acyl or trifluoromethyl and Xis --CH₂ -- and n is 0, 1, 2 or 3, or X is --CO-- and n is 1, 2 or 3, orX is --O-- and n is 2 or 3, and acid addition salts thereof.

In another group of compounds of formula I A is N, B is CH, Z is a ringof formula II, R₁, R₂ and R₃ are each, independently, hydrogen or(C₁₋₄)alkyl, m is 1, R₄ and R₅ are each, independently, hydrogen,halogen, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₂₋₄)acyl or trifluoromethyl and Xis --CH₂ -- and n is 0, 1, 2 or 3, or X is --CO-- and n is 1, 2 or 3, orX is --O-- and n is 2 or 3, and acid addition salts thereof.

Another group of compounds comprises compounds of formula I wherein A isCH, B is N, Z is a ring of formula III, R₁ ', R₂ ' and R₃ are eachindependently, hydrogen or (C₁₋₄) alkyl, m is 1, R₄ and R₅ are each,independently, hydrogen, halogen, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₂₋₄)acylor trifluoromethyl and X is --CH₂ -- and n is 0, 1, 2 or 3, or X is--CO-- and n is 1, 2 or 3, or X is --O-- and n is 2 or 3, and acidaddition salts thereof.

In another group of compounds of formula I A is N, B is CH, Z is a ringof formula III, R₁ ', R₂ ' and R₃ are each, independently, hydrogen or(C₁₋₄)alkyl, m is 1, R₄ and R₅ are each, independently, hydrogen,halogen, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₂₋₄)acyl or trifluoromethyl and Xis --CH₂ -- and n is 0, 1, 2 or 3, or X is --CO-- and n is 1, 2 or 3, orX is --O-- and n is 2 or 3, and acid addition salts thereof.

Another group of compounds comprises compounds of formula I wherein oneof A and B is N and the other CH, Z is a ring of formula II, R₁ and R₂are each, independently, hydrogen or (C₁₋₄)alkyl, R₃ is hydrogen, R₄ ishydrogen or halogen, R₅ is hydrogen, X is --CH₂ -- and n is 0 or 1 or Xis --CO-- and n is 3 or X is --O-- and n is 3 or an acid addition saltthereof.

Another group of compounds comprises compounds of formula I wherein oneof A and B is N and the other CH, Z is a ring of formula III, R₁ ' andR₂ ' are either the same and signify hydrogen or (C₁₋₄)alkyl or R₁ ' andR₂ ' together signify tetramethylene, R₃ is hydrogen, m is 1, R₄ ishalogen, R₅ is hydrogen, X is --CO-- and n is 3 or X is --O-- and n is3, or an acid addition salt thereof.

In a first group of compounds A is CH, B is N and Z is a ring of formulaII.

In a second group of compounds A is N, B is CH and Z is a ring offormula II.

In a third group of compounds A is CH, B is N and Z is a ring of formulaIII.

In a fourth group of compounds A is N, B is CH and Z is a ring offormula III.

In a fifth group of compounds R₁ is hydrogen.

In a sixth group of compounds R₁ is (C₁₋₆)alkyl.

In a seventh group of compounds R₁ is (C₇₋₁₀)phenylalkyl.

In a eighth group of compounds R₂ is hydrogen.

In a nineth group of compounds R₂ is (C₁₋₆)alkyl.

In a tenth group of compounds R₂ is (C₇₋₁₀)phenylalkyl.

In a eleventh group of compounds R₃ is hydrogen.

In a twelvth group of compounds R₃ is (C₁₋₄)alkyl.

In a thirteenth group of compounds R₁ ' and R₂ ' are hydrogen.

In a fourteenth group of compounds R₁ ' and R₂ ' are (C₁₋₄)alkyl.

In a fifteenth group of compounds m=1.

In a sixteenth group of compounds X is --CH₂ --.

In a seventeenth group of compounds X is --CO--.

In a eighteenth group of compounds X is --O--.

In a nineteenth group of compounds R₄ is hydrogen.

In a twentienth group of compounds R₄ is halogen.

In a twenty-first group of compounds R₅ is hydrogen.

What we claim is:
 1. A compound of formula I, ##STR17## wherein one of Aand B is N and the other CH, R₁ and R₂ are each, independently,hydrogen, (C₁₋₆)-alkyl or (C₇₋₁₀)phenylalkyl, optionally monosubstitutedin the phenyl ring by halogen, (C₁₋₄)alkyl or (C₁₋₄)alkoxy,R₃ ishydrogen or (C₁₋₄)alkyl, m is 1 or 2, R₄ and R₅ are each, independently,hydrogen, halogen, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₂₋₄)acyl ortrifluoromethyl, and X is --CH₂ -- and n is 0, 1 2 or 3, or X is --CO--and n is 1, 2 or 3, or X is --O-- and n is 2 or 3, or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A compound of claim 1 whereinA is CH, B is N, R₁, R₂ and R₃ are each, independently hydrogen or(C₁₋₄)alkyl, m is 1, R₄ and R₅ are each, independently, hydrogen,halogen (C₁₋₄)alkyl, (C₁₋₄)alkoxy, (C₂₋₄)acyl or trifluoromethyl and Xis --CH₂ -- and n is 0, 1, 2 or 3, or X is --CO-- and n is 1, 2 or 3, orX is --O-- and n is 2 or 3, or a pharmaceutically acceptable acidaddition salt thereof.
 3. A compound of claim 1 wherein A is N, B is CH,R₁, R₂ and R₃ are each, independently, hydrogen or (C₁₋₄)alkyl, m is 1,R₄ and R₅ are each, independently, hydrogen, halogen, (C₁₋₄)alkyl,(C₁₋₄)alkoxy, (C₂₋₄) acyl or trifluoromethyl and X is --CH₂ -- and n is0, 1, 2 or 3, or X is --CO-- and n is 1, 2 or 3, or X is --O-- and n is2 or 3, or a pharmaceutically acceptable acid addition salt thereof. 4.A compound of claim 1 which is1-(4-fluorophenyl)-4-[4-(1H-imidazo[4,5-b]pyridin-5-yl)-1-piperazinyl]-1-butanone,or a pharmaceutically acceptable acid addition salt thereof.
 5. Acompound of claim 1 which is1-(4-fluorophenyl)-4-[4-(2-ethyl-1H-imidazo[4,5-b]pyridin-5-yl)-1-piperazinyl]-1-butanoneor a pharmaceutically acceptable acid addition salt thereof.
 6. Apharmaceutical composition useful in treating schizophrenia,hypertension and cardiac disorders comprising a pharmaceuticallyacceptable carrier or diluent and a therapeutically effective amount ofa compound of claim 1, or a pharmaceutically acceptable acid additionsalt thereof.